Field of the Invention
The present disclosure relates to the fields of molecular biology, ophthalmology, and gene therapy. In particular embodiments, capsid-mutated rAAV vectors and methods for their use in gene therapy are disclosed. In exemplary embodiments, capsid proteins comprising a modification of one or more of the surface-exposed tyrosine residues are disclosed, including VP3 capsid proteins that include tyrosine-to-phenylalanine mutations at positions corresponding to Y444F, Y500F, and Y730F of the wild-type AAV2 sequence. Also provided are rAAV virions and viral particles that comprise such a mutated AAV capsid protein and a nucleic acid molecule that expresses one or more selected therapeutic or reporter transgenes in one or more mammalian cells of interest.
Description of Related Art
A gene-delivery therapy to treat a disease or disorder independent of treating an underlying mutation could have potential value. Methods capable of controlling, regulating, and/or driving specific neural circuits so as to mediate naturalistic neural responses and high resolution perception and control could also be of enormous potential therapeutic value. Neurons are an example of a type of cell that uses the electrical currents created by depolarization to generate communication signals (e.g., nerve impulses). Other electrically excitable cells include skeletal muscle, cardiac muscle, and endocrine cells. Neurons use rapid depolarization to transmit signals throughout the body and for various purposes, such as motor control (e.g., muscle contractions), sensory responses (e.g., touch, hearing, and other senses) and computational functions (e.g., brain functions). By facilitating or inhibiting the flow of positive or negative ions through cell membranes, the cell can be briefly depolarized, depolarized and maintained in that state, or hyperpolarized. Thus, the control of the depolarization of cells can be beneficial for a number of different purposes, including visual, muscular and sensory control. Light-sensitive protein channels, pumps, and receptors can permit millisecond-precision optical control of cells. Although light-sensitive proteins in combination with light can be used to control the flow of ions through cell membranes, targeting and delivery remain to be addressed for specific diseases, disorders, and circuits.